Reprinted by permission of Nasr Anaizi
The Drug Monitor

Once-Daily Dosing of Aminoglycosides

A Consensus Document
Nasr Anaizi, Ph.D.
Revised Apr 25th 1997

NOTE: Since the publication of this article {International J. Clin Pharmacol & Therap 1997; 35(6):223-226} sufficient experience lead to the conclusion that a q48h pulse dosing regimen is NOT recommended. Therefore, the dosing table and monitoring graph have been modified to reflect this change. Also, many of our young patients (18 - 39 yrs) with excellent renal function (CLcr>100 mL/min) require a q12h pulse dosing regimen. A new dosing algorithm for this subpopulation is under study.

Background Clinical Studies
Rational The Post-Antiobiotic Effect
Concentraton-dependent Kill Rate Adaptive Post-Exposure Resistance
Advantages of Extended-interval Dosing Dosing and Monitoring Guidelines

Since their introduction into clinical use 50 years ago and despite the advent of newer agents (carbapenems, monobactams, and fluoroquinolones) , aminoglycoside antibiotics (AGAs) continue to play an important role in the treatment of severe infections, particularly those due to aerobic, Gram-negative bacilli (GNB). Several factors account for their durability and continued clinical usefulness: therapeutic efficacy, synergy with the ß-lactam antibiotics, low rate of development of true resistance, and low drug cost. Their main drawback has been the occurrence of (reversible) nephrotoxicity and ototoxicity in a significant number of patients (5 - 25%).
Traditionally, aminoglycosides are administered in multiple daily doses (once every 8 or 12 hrs). However, clinicians worldwide are becoming increasingly aware that the standard "80 mg every 8 hrs" regimen is no longer an acceptable practice. Clinical experience over the past 50 years has shown the multiple daily dosing strategy to be both labor- and lab-intensive. Correct multiple daily dosing of aminoglycosides often requires pharmacokinetics expertise and close monitoring of drug serum levels and renal function. Therapeutic drug monitoring has been used extensively to guide dosage adjustments to maximize efficacy and minimize toxicity. Aminoglycoside-associated therapeutic monitoring usually accounts for most of the cost of aminoglycoside therapy. It is not unusual to see three or more sets of peak/trough levels taken during a single gentamicin therapy course lasting less than ten days. In addition, there are other important problems associated with the standard dosing of aminoglycosides - sub-therapeutic dosing (low peaks) , inconvenience for patients due to frequent administration, inaccurate timing of drug administration and blood sampling, and misinterpretation of drug levels.
The multiple daily dosing regimen is based on the assumption that therapeutic efficacy requires that the serum level of the antimicrobial agent be maintained above the minimum inhibitory concentration (MIC) for the target organism at all times during the course of therapy. The validity of this assumption for aminoglycosides has been strongly challenged during the past decade. During this period a rapid evolution in aminoglycoside dosing strategies has taken place. The primary aim of these changes is not only to minimize toxicity but also reduce treatment failure, morbidity, and mortality.
The high-peak-extended-interval dosing of aminoglycosides has also been called "once-daily" or "single-daily" and "pulse" dosing. It was first used by Labovitz (1) in 1974 and then rediscovered by several groups during the 1980s. Due to its ease and comparable safety and efficacy it quickly gained popularity worldwide. A survey conducted in 1994 by Schumock and co-workers (2) estimated that in the USA over 27% of hospitals of 400 beds or larger used the once-daily dosing routinely. Currently many centers are adopting the "once-daily aminoglycosides" (or ODA ) as their standard / preferred dosing method for aminoglycosides. By the year 2000, this figure may be as high as 80%.

As of Apr '97, over 50 human clinical trials dealing with the "once-daily dosing of aminoglycosides" have been published. Over 20 of these represent randomized studies involving collectively > 3000 patients. The vast majority of these trials failed individually to find a significant difference between the single and multiple dosing regimens largely because of the limited number of patients involved in a single trial. Therefore, to the enhance statistical power, data from individual trials were pooled for meta-analysis by at least four independent groups. In a statistical study published in 1995, Galloe and co-workers (3) analyzed the results of trials involving a total of about 1200 patients. They concluded that there is no significant difference in either efficacy or safety between the single-dose and the multiple-dose regimes. However the results of the three meta-analyses published in 1996 (4, 5, 6) which included data from a much larger pool of patients clearly favor the high-peak-extended-interval dosing strategy. Ferriols-Lisart and Alos-Alminana (4) analyzed the results of 18 randomized, clinical trials involving a total of 2317 patients. They concluded that pulse dosing is therapeutically more effective (odds ratio = 1.47) and less nephrotoxic (odds ratio = 0.60). Similarly, Barza and coworkers (5) concluded that, compared to multiple dosing, the single daily administration of aminoglycosides to patients without pre-existing renal impairment is at least as effective, has a significantly lower risk of nephrotoxicity, and no greater risk of ototoxicity. It was also observed that the efficacy of pulse dosing was superior in those clinical trials with a higher percentage of Pseudomonas isolates. Hatal and co-workers (6) evaluated 17 randomized trials comparing once-daily versus the standard dosing in 3,089 infected, immuno-competent adults. Even taking into consideration the heterogeneity of the pooled studies, the meta-analysis still indicated that the two regimens are equal in therapeutic efficacy, but that the pulse dosing was superior in terms of safety. The relative risks of nephrotoxicity and ototoxicity were found to be respectively 13% and 33% lower with pulse dosing. These conclusions are further supported by several individual clinical trials, whose results strongly suggest that the single daily dosing regimen significantly reduces the risk for nephrotoxicity (7-9) and ototoxicity (10, 11).

The rational for the pulse dosing of aminoglycosides is rooted in the following observations:

  1. Aminoglycosides exhibit a significant post-antibiotic effect (PAE) against aerobic GNB both in vitro and in vivo (12) The PAE refers to the continued suppression of bacterial growth despite the decline of the antimicrobial concentration to zero. The duration of this effect (2 - 8 hrs) depends on several factors, chief among them is the height of the preceding aminoglycoside peak. The PAE phenomenon suggests that the aminoglycoside serum level may be allowed to fall below the MIC of the pathogen without compromising antimicrobial efficacy. The PAE lasts longer in vivo than in vitro, and its duration in vivo may be dependent on host factors. Animal studies suggest that the PAE duration may be shortened by neutropenia. In addition, in vitro studies suggest that the aminoglycoside PAE is extended by the addition of a ß-lactam antibiotic.
  2. The bactericidal action of aminoglycosides is concentration dependent, i.e., the higher the peak/MIC ratio the higher the kill rate (13). The multiple daily dosing regimen usually results in relatively low peak/MIC ratios (<5 ), but when the same total daily dose is given as a single bolus (infused over 30-60 minutes), much higher ratios are obtained (>10). Adult and pediatric patients receiving single-daily doses of amikacin showed significantly higher cure rates than those receiving multiple daily doses (14).
  3. Aminoglycoside uptake into renal tubule cells and the inner ear appears to be saturated at relatively low serum levels, suggesting that higher peaks do not necessarily result in a greater risk of toxicity. Also, serum troughs that are at or near zero may promote tissue drug disposition, shorten tissue exposure, and promote recovery. In addition to the well known risk factors (age, volume depletion, liver disease, co-administration of certain drugs, etc.), duration of exposure to the aminoglycoside appears to be a more important determinant of toxicity than the serum aminoglycoside level. Although definitive evidence is still lacking, animal and human studies strongly suggest that pulse dosing is less nephrotoxic. Further, when the data of 17 clinical studies are considered together, the conclusion that the pulse dosing of aminoglycosides is safer is inevitable (6).
  4. In vitro studies indicate that more frequent dosing of aminoglycosides tends to reduce their uptake into the bacterial cell of aerobic GNB. This phenomenon ("adaptive post-exposure resistance") is observed as an apparent increase in the MIC90 (i.e., reduced efficacy). Longer dosing intervals appear to shorten the time required for the MIC to revert to its original value (15). These observations may have significant clinical implications - persistent low level exposure of the target organism as occurs with multiple daily dosing may markedly reduce the antimiccrobial activity of aminoglycosides

During the last five years, over a hundred articles have been published on the topic of aminoglycoside dosing including reports of original clinical trials, in vitro studies, animal studies, accounts of clinical experience (16), meta-analyses (3 - 6), book chapters (17), surveys (2), newsletters, and review articles (18 - 20). There appears to be a general consensus that pulse dosing of aminoglycosides offers the following advantages:

Guidelines for The Pulse Dosing of Aminoglycosides

Eligible Patients:
All adult patients requiring aminoglycoside therapy except:

    1. Pregnant patients;
    2. Patients with extensive burn (>20% of body surface area)
    3. Patients with severe liver disease (e.g., ascites);
    4. Patients with severe renal disease (CLcr < 30 mL/min);
    5. Neutropenic patients;
    6. Patients with enterococcal endocarditis;
    7. Patients with Gram positive infections (when the aminoglycoside is used for synergy);
    8. Patients with a history of allergy to aminoglycosides;
    9. Patients with a history or signs of a hearing loss or vestibular dysfunction.
Also, pulse dosing of aminoglycosides has not been well studied in children and cannot yet be recommended for this population.

Dosage
The single dose for gentamicin and tobramycin is 5 mg per kg of actual body weight (ABW) unless the patient is >20% heavier than the ideal body weight (IBW). For obese patients, a dosing weight should be calculated (see equations below). The calculated dose is diluted in 100 mL of normal saline and infused over one hour. Doses as high as 7 mg/kg have been used, but there no evidence that doses >5 mg/kg offer any advantage. For amikacin, the dose is 20 mg/kg.

The initial dosing interval is determined by the creatinine clearance (CLcr):

CLcr (mL/min) >60 40-59
Dosing interval 24 hrs 36 hrs

The main objectives of the pulse dosing strategy are to:

    1. achieve a high aminoglycoside peak (>10 x MIC) to maximize efficacy.
    2. allow a drug-free interval of 3 - 5 hours to minimize toxicity and permit the reversal of the adaptive post-exposure resistance.

Some clinicians express the concern that in patients with low creatinine clearance (CLcr < 40 mL/min) the aminoglycoside level may remain significantly elevated (> 2 mg/L) for long periods of time which would further damage the kidneys. Thus, if a dosing interval longer than 48 hours would be necessary to achieve the 2nd objective (above), then an alternative antimicrobial agent should be considered. Also, in patients with high clearance (e.g., young adults, cystic fibrosis, burns, etc) dosing intervals shorter than 24 hrs may be more appropriate.

Monitoring
A baseline serum creatinine (Scr) is necessary before initiating aminoglycoside therapy. Thereafter, Scr should be rechecked at least once every week. In patients with adequate renal function (CLcr >60 mL/min), a trough aminoglycoside level (taken during the last hour of the dosing interval) should be near zero (<<1 mg/L). If this is found to be the case, the initial dosing interval may be maintained and no further drug levels are necessary as long as CLcr remains unchanged. If the trough level is > 1, an extension of the dosing interval will be necessary. Alternatively, an accurately timed random level may be obtained 7 - 14 hrs after the end of infusion. To determine the proper dosing interval, the reported random level is plotted on a special graph, which is applicable to the gentamicin, netilmicin, and tobramycin.

Dosing intervals longer than 36 hours are not recommended. In such cases, alternative therapies (e.g., a fluoroquinolone) should be considered.

It should be noted that the choice of a 24-hrs dosing interval for patients with CLcr > 60 mL/min has been dictated primarily by convenience rather by pharmacokinetic considerations. Indeed a 12 hourly dosing regimen may be more appropriate for young patients with CLcr >100 mL/min or when the non-renal aminoglycoside clearance is elevated as in cystic fibrosis patients (21). Using the 24-hrs dosing interval in these patients, the aminoglycoside level is likely to be nil for a period exceeding the duration of the PAE.

Ideally, the peak-to-MIC ratio should be > 10, which is easily achieved in most patients. Therefore, there is usually no need to measure the peak level except in patients with markedly expanded volume of distribution. In these patients higher doses may be necessary to achieve an adequate peak-to-MIC ratio.

References
  1. Labowitz E, Levison ME, Kay D. Single dose daily gentamicin therapy in urinary tract infection. Antimicrob agents Chemother. 1974; 6:465-470.
  2. Schumock GT, Raber SR, Crawford SY, et al. National Survey of Once-Daily Dosing of Aminoglycoside Antibiotics. Pharmacotherapy 1995; 15:201-209
  3. Galloe AM, Graudal N, Christensen HR, Kampmann JP. Aminoglycosides: single or multiple daily dosing? A meta-analysis on efficacy and safety. Eur J Clin Pharmacol 1995; 48: 39-43
  4. Ferriols-Lisart and Alos-Alminana. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health-Syst Pharm.1996; 53:1141-50.
  5. Barza Ioanidis JPA, Cappelleri et al Single or multiple daily doses of aminoglycosides - a meta-analysis BMJ 1996; 312:338-345
  6. Hatala et al. Once-daily Aminoglycoside Dosing in Immunocompetent Adults: A Meta Analysis. Ann Intern Med 1996;124:717-725
  7. Ter Braak EW, De Vries PJ, Bouter KP et al. Once daily dosing regimen for aminoglycoside plus beta-lactam combination therapy for serious infections: comparative trial with netilmicin plus ceftriaxone. Am J Med. 1990; 89: 58-66.
  8. Prins JM, Buller HB, Kuijper EJ et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341: 335-339.
  9. Marik PE, Havlik I, Monteagudo FSE, Lipman J. Pharmacokinetics of amikacin in critically ill adult and pediatric patients: comparison of once- versus twice-daily dosing regimens. J Antimicrob Chemother. 1991; 27 (Suppl C):81-89.
  10. Tran Ba Huy, Deffrennes D. Aminoglycoside toxicity - influence of dosage regimen on drug uptake and correlation between drug binding and some clinical features. Acta Otolaryngol. 1988; 105:511-515
  11. Pettarossi VE, Ferraresi A, Errico P et al. Impact of different dosing regimens of the aminoglycosides netilmicin and amikacin on vestibulotoxicity in the guinea pig. Eur Arch Otolaryngol. 1990; 247:277-282.
  12. Craig WA, Gudmundson S. The postantibiotic effect. In: Loran V, ed. Antibiotics in laboratory medicine 3rd ed. Baltimore: Williams & Wilkins: 1991:403-431.
  13. Moore RD, Smith CR, Lietman PS. Associate of aminoglycoside plasma levels with therapeutic outcome Gram-negative pneumonia. Am J Med. 1984; 77:657-662.
  14. Marik PE, Lipman J, Kobilski S, et al . A prospective randomized study comparing once vs twice daily amikacin dosing in critically ill adult and pediatric patients. J Antimicrob Chemother. 1991; 28:753-764.
  15. Karlowsky JA, Zhanel GG, Davidson RJ, et al. Once-daily aminoglycoside dosing assessed by MIC reversion time with Pseudomonas aerugenosa. Antimicrob Agents Chemother. 1994; 38:1165-1168.
  16. Nicolau DP, Freeman CD, Belliveau PP et al. Experience with a once-daily aminoglycoside program administered to 2184 adult patients. . Antimicrob Agents Chemother. 1995; 39:650-655.
  17. Gilbert DN. Aminoglycosides. In Mandel GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. 4th ed. 1995 Churchill Livingston, New York
  18. Barclay ML, Begg EJ, Hinckling KG. What is the evidence for once daily aminoglycoside therapy? Clin Pharamcokinet 1994; 27:32-48
  19. Beggs EJ, Barclay ML. Aminglycosides - 50 years on. Br. J. Clin Pharmacol 1995; 39:597-603.
  20. Preston SL, Briceland LL. Single Daily Dosing of Aminoglycosides. Pharmacotherapy 1995; 15:297-316.
  21. Wood PJ, Ioannides-Demos LI, Li SC, et al. Minimisation of aminoglycoside toxicity in patients with cystic fibrosis. Thorax 1996; 51:369-373

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